Oxazoloquinoline compounds and therapeutic application thereof

ABSTRACT

The present invention relates to tricyclic carbamates coplying with the formula   &lt;IMAGE&gt; (I)  in which n=0, 1 or 2, p=0 or 1, R1 represents a hydrogen atom; a group which is alkyl in C1-C4; a phenyl group; a group which is alkenyl in C2-C3; or a methyl group substituted by a hydroxy group, a group which is alkoxy in C1-C4, an amino group or an N-alkylamino or N,N-dialkylamino group where the alkyl radical is in C1-C4, and R2 represents a hydrogen atom; a halogen atom; a group which is alkyl in C1-C4, or a group which is alkoxy in C1-C4, and their salts of addition of acid. These compounds are therapeutically useful, notably as antidepressant agents.

The present invention relates to novel tricyclic carbamates, a method ofpreparation and therapeutic application thereof, notably asantidepressant agents.

The tricyclic carbamates according to the invention comply moreprecisely with the formula ##STR2## in which: n=0, 1 or 2,

p=0 or 1,

R₁ represents a hydrogen atom; a group which is alkyl in C₁ -C₄ ; aphenyl group; a group which is alkenyl in C₂ -C₃ ; or a methyl groupsubstituted by a hydroxy group, a group which is alkoxy in C₁ -C₄, anamino group or a N-alkylamino or N,N-dialkylamino group where the alkylradical is in C₁ -C₄, and

R₂ represents a hydrogen atom; a halogen atom; a group which is alkyl inC₁ -C₄ ; or a group which is alkoxy in C₁ -C₄.

The present invention also relates to the salts of addition of mineralacid such as hydrochloric acid or organic acid such as a carboxylicacid, of the carbamates of formula (I) having a group which issalifiable by such an acid.

It should be noted that in the foregoing and hereafter the expression"alkyl in C₁ -C₄ " comprises groups with a straight or branched chainhaving up to 4 atoms of carbon, namely methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and tert-butyl; the expression "alkenyl in C₂-C₃ " encompasses the vinyl, propenyl, i-propenyl and allyl groups; andthe expression "alkoxy in C₁ -C₄ " complies with the formula -O-alkyl inC₁ -C₄.

It will also be noted that the compounds of formula (I) have one or twoasymmetric atoms of carbon depending on whether or not R₁ represents ahydrogen atom. Thus these compounds can exist in a certain number ofstereoisomeric forms, including enantiomers. Thus the present inventionextends to each of these stereoisomeric forms, including enantiomers, aswell as mixtures thereof, including racemates.

The method of preparation of the tricyclic carbamates of formula (I) ischaracterised in that it includes

(i) the cyclisation, by ethyl carbonate and in the presence of a base(for example an alcoholate of alkaline metal such as an alcoholate ofsodium) or by phosgene, and preferably in an aprotic organic solventsuch as toluene, of compounds of the formula ##STR3## in which n, p andR₂ have the same significance as in formula (I) defined above and R₃represents a hydrogen atom, a group which is alkyl in C₁ -C₄, a groupwhich is alkenyl in C₂ -C₃ or a phenyl nucleus, or

the intramolecular cyclisation in the presence of a base (for example analcoholate of alkaline metal such as an alcoholate of sodium), andpreferably in an aprotic organic solvent such as toluene, of compoundsof the formula ##STR4## in which n, p, R₂ and R₃ have the samesignificance as in formula (II) above, which leads to compounds of theformula ##STR5## in which n, p, R₂ and R₃ have the same significance asin formula (II).

(ii) possibly ozonolysis of the compounds of formula (Ia) for which R₃represents a CH═CH₂, this ozonolysis being followed by reductionpreferably by a metal hydride, which leads to compounds of the formula##STR6## where n, p and R₂ have the same significance as in formula(Ia).

(iii) possibly the action of an alkylation agent, preferably a di(alkylin C₁ -C₄) sulphate, in the presence of a phase transfer catalyst suchas tetrabutyl ammonium bromide, on the CH₂ OH radical of the compoundsof formula (Ib) in order to obtain compounds of the formula ##STR7##where n, p and R₂ have the same significance as in formula (Ib) and R₄represents a group which is alkoxy in C₁ -C₄, and

(iv) possibly the action of a mesyl or tosyl halide on the compounds offormula (Ib), followed by the action either of sodium borohydride indimethylsulphoxide, or of NH₃ or a mono- or dialkylamine of which thealkyl radical or radicals are in C₁ -C₄, on the resulting mesylates ortosylates, which leads to compounds of the formula ##STR8## where n, pand R₂ have the same significance as in formula (Ib) and R₅ represents ahydrogen atom, an amino group or an alkylamino or dialkylamino group ofwhich the alkyl radical or radicals are in C₁ -C₄.

The compounds of formula (II) are obtained (a) by the action oftert-butyllithium, preferably in an aprotic solvent (for example THF),on compounds of the formula ##STR9## in which n and R₂ have the samesignificance as in formula (I) and P represents a protective group ofthe nitrogen atom which is capable of activating the position in α ofthis nitrogen atom, (b) the action on the carbanion thus formed of analdehyde of the formula

    R.sub.3 CHO                                                (V)

or an epoxy of the formula ##STR10## R₃ having in formulae (V) and (VI)the same significance as in formula (II), which leads to alcohols of theformula ##STR11## where n, p, R₂ and R₃ have the same significance as informula (II), then (c) the deprotection of these alcohols (VII).

Advantageously the protective group P has the formula ##STR12## and inthis case the deprotection is obtained by alkaline treatment in analcoholic medium, by treatment with double hydride of lithium andaluminium in ether or by treatment with hydrazine in an alcoholicmedium, which gives rise to compounds of the formula (II).

As regards the compounds of formula (IV), these are prepared in a knownmanner from corresponding indolins, tetrahydro-1,2,3,4 quinolines andtetrahydro-2,3,4,5 benzazepines. Thus, when P has the particular formulamentioned above, the protocol described by A. I. MEYERS, S. HEURING inTetrahedron Lett., (1981), 22, 5119, can be put into effect.

The compounds of formula (III) for which R₃ represents a group which isalkyl in C₁ -C₄, a group which is alkenyl in C₂ -C₃ or a phenyl nucleus,are obtained by action of an organic magnesium or organic lithiumcompound in which the metal is bound to a group which is alkyl in C₁-C₄, a group which is alkenyl in C₂ -C₃ or a phenyl nucleus, oncompounds of the formula ##STR13## where n, p and R₂ have the samesignificance as in formula (I), followed by hydrolysis.

The compounds of formula (III) for which R₃ represents a hydrogen atomare obtained by reduction by hydrogen in the presence of a Pd/C catalystof compounds of formula (VIII) defined above.

The compounds of formula (VIII) are obtained

(a) either by conversion by Raney nickel in the presence of sodiumhypophosphite of tetrahydroquinolines of the formula ##STR14## where n,p and R₂ have the same significance as in formula (I),

(b) or by oxidation by oxalyl chloride in the presence of DMSO andtriethylamine of compounds of the formula ##STR15## where n, p and R₂have the same significance as in formula (I).

The compounds of formula (IX) for which p=0 and n=0, 1 or 2 are obtainedby the action of trimethylsilyl cyanide in the presence of a Lewis acidsuch as AlCl₃ in an aprotic organic solvent such as dichloroethane oncompounds of the formula ##STR16## where n and R₂ have the samesignificance as in formula (I).

The compounds of formula (IX) for which p=0 and n=1 can as a variant beobtained by hydrogenation in the presence of a hydrogenation catalystsuch as palladium on barium sulphate or calcium carbonate of compoundsof the formula ##STR17## where R₂ has the same significance as informula (I), these compounds of formula (XII) being, for their part,obtained by the method described in Synthesis (1977), 497.

The compounds of formula (IX) for which p=1 and n=0, 1 or 2 are obtainedby the action of a mesyl or tosyl halide on the compounds of formula (X)for which p=0, then subjecting the mesylates or tosylates thus obtainedto the action of an alkaline metal cyanide such as sodium cyanide.

As regards the salts of the carbamates of formula (I), they are forexample obtained by the action of a mineral or organic acid, in solutionin an appropriate solvent, on a solution in an appropriate solvent ofcarbamates having a salifiable group, notably an amino, alkylamino ordialkylamino group.

Finally, it should be noted that the different stereoisomeric forms canbe separated from one another by the usual methods and notably by liquidchromatography in particular on a column of silica.

The following preparations are given by way of examples to illustratethe invention.

EXAMPLE 1 (tert-butyliminomethyl)-1 methoxy-6 (hydroxy-3 propen-1yl-3)-2 tetrahydro-1,2,3,4 quinoline [(VII), R₂ =2-OCH₃, R₃ : CH═CH₂,n=1, p=0].

The (tert-butyliminomethyl)-1 methoxy-6 tetrahydro-1,2,3,4 quinoline(50.5 g, 0.205 mole) is dissolved in 300 ml of tetrahydrofuran. Thesolution is cooled to -78° C. and the tert-butyllithium 1.7N in pentane(300 ml, 0.51 mole) is added drop by drop. The reaction medium isagitated for 1 h at a temperature of between -15° C. and -20° C. beforebeing cooled again to -78° C. Acrolein (18 ml, 0.27 mole) in solution in30 ml of tetrahydrofuran is added at this temperature. After 1 h ofagitation, the medium is hydrolysed by the addition of 300 ml of water.After returning to ambient temperature, the medium is extracted withthree times 300 ml of methylene chloride. The organic phases arecollected, dried on sodium sulphate and evaporated. The product isutilised crude without any other purification in example 2.

EXAMPLE 2 methoxy-6 (hydroxy-3 propen-1 yl-3)-2 tetrahydro-1,2,3,4quinoline [(II), R₂ =2-OCH₃, R₃ : CH═CH₂, n=1, p=0, code MD 280 402]

The crude product of example 1 is dissolved in 500 ml of methanol and asolution of potassium hydroxide 2N (1160 ml, 10 equivalents) is added.After 2 h of agitation to reflux of the solvent, the medium is extractedby two times 500 ml of methylene chloride. The product is extracted fromthe organic phases by two times 500 ml of a hydrochloric acid solution3N, the aqueous phases obtained are alkalinised by a concentratedsolution of sodium hydroxide and the product extracted by three times500 ml of methylene chloride. After drying on sodium sulphate andevaporation of the solvent, 37 g of an oil was obtained which ispurified on a column of alumina and eluted with isopropyl ether thenwith ethyl acetate.

¹ H NMR (CDCl₃) δ in ppm: 6.5 (3H, broad singlet): 5.8 (1H, multiplet);5.3 (2H, multiplet); 4.0 (1H, multiplet); 3.6 (3H, singlet); 3.0-3.4(2H+1H exchangeable); 2.6-2.9 (2H); 1.6 to 2.0 (2H).

In the same manner, but from appropriate starting materials, the othercompounds of formula (II) are obtained, notably:

(hydroxy-3 propen-1 yl-3)-2 indolin [R₂ =H, R₃ : CH═CH₂, n=0, p=0, code:MD 200 599] in the form of oil.

¹ H NMR (CDCl₃) δ in ppm: 2.5 (2H); 2.9 (2H); 3.6 to 4.2 (2H); 5 to 6.2(3H); 6.4 to 7.2 (4H).

(hydroxy-3 propen-1 yl-3)-2 tetrahydro-1,2,3,4 quinoline [R₂ =H, R₃ :CH═CH₂, n=1, p=0, code: MD 200 501] in the form of oil.

¹ H NMR (CDCl₃) δ in ppm: 1.6 to 2.2 (2H); 2.7 (2H); 3.2 (2H); 4 (2H); 5to 5.2 (3H); 6.4 to 7.2 (4H).

EXAMPLE 3 ethenyl-3 methoxy-7 tetrahydro-3,3a, 4,5 1H-oxazolo [3.4-a]quinoline-one-1 [(Ia), R₂ =2-OCH₃, R₃ : CH═CH₂, n=1, p=0, cis, code: MD280 403] and [(Ia), R₂ =2-OCH₃, R₃ : CH═CH₂, n=1, p=0, trans, code: MD280 404]

The product of example 2 (10.5 g, 48 mmoles) is dissolved in 100 ml oftoluene in the presence of diethyl carbonate (6.5 g, 55 mmoles). Themedium is rendered anhydrous by azeotropic distillation of a part oftoluene. The heat source is temporarily withdrawn and, at 100° C., asolution of sodium methylate 4N in methanol (1.2 ml, 4.8 mmoles) isadded. The ethanol formed by the cyclisation reaction is distilled inazeotropic form with toluene towards 75°-78° C. When the temperature ofthe distillate reaches 110° C. the reaction is terminated. The solventis evaporated in vacuo. The mixture of diastereoisomers obtained is thensubjected to chromatography on silica using a n-heptane/ethyl acetate70/30 eluent system.

The least polar product (MD 280 404) consisting of the racemic pair ofdiastereoisomers of trans relative configuration is eluted first: afterevaporation of the elution solvents and recrystallisation in isopropylether, 2.9 g of this racemic is obtained.

The most polar product (MD 280 403) consisting of the racemic pair ofdiastereoisomers of cis relative configuration is eluted second: afterevaporation of the solvents, 3.8 g (white solid) of this racemic isobtained.

EXAMPLE 4 cyano-2 dihydro-1,2 methyl-7 quinolinecarboxylate-1 of ethyl[(XII), R₂ =3-CH₃, code: MD 370 236]

To a solution cooled to 0° C. of 0.6 mole (9.1 g) of methyl-7 quinolinein 110 ml of methylene chloride, 0.063 mole (8.5 ml) of trimethylsilylcyanide is added in 5 minutes then in 5 minutes 0.063 mole (6.1 ml) ofethyl chloroformate and 0.44 g of aluminium chloride is added. Afterreturning to ambient temperature, the reaction medium is poured ontowater. The organic phase is washed with water, dried on sodium sulphateand concentrated. The product is purified by flash chromatography onsilica (eluent: isopropyl ether/petroleum ether 50/50). 13.4 g ofexpected product is obtained, that is to say a yield of 87% (meltingpoint 87° C.).

The following are obtained in the same way:

cyano-2 dihydro-1,2 methoxy-6 quinolinecarboxylate-1 of ethyl: [(XII),R₂ =2-OCH₃, code: MD 280 523]; melting point=89° C.

cyano-2 dihydro-1,2 quinolinecarboxylate-1 of ethyl: [(XII), R₂ =H,code: MD 280 441]; melting point=82° C.

chloro-7 cyano-2 dihydro-1,2 quinolinecarboxylate-1 of ethyl [(XII), R₂=2-Cl, code: MD 370 329]; oil.

EXAMPLE 5 cyano-2 tetrahydro-1,2,3,4 quinolinecarboxylate-1 of ethyl[(IX), R₂ =H, n=1, p=0, code: MD 280 442]

Cyano-2 dihydro-1,2 quinolinecarboxylate-1 of ethyl (56.3 g, 0.24 mole)dissolved in 500 ml of methanol is subjected to hydrogenolysis under apressure of 5 kg/cm₂ (approximately 5.10⁵ Pa) of hydrogen in thepresence of 5% palladium on barium sulphate (5.6 g) at 40° C. for 2 h.The catalyst is eliminated by filtration, the solvent evaporated invacuo and the residue crystallised in isopropyl ether. 48 g of a whitesolid corresponding to the expected product and having a melting pointof 84° C. are obtained.

The following are obtained in the same way:

cyano-2 methyl-7 tetrahydro-1,2,3,4 quinolinecarboxylate-1 of ethyl[(IX), R₂ =3-CH₃, n=1, p=0, code: MD 370 237]; yield=80%; meltingpoint=110° C.

cyano-2 methoxy-6 tetrahydro-1,2,3,4 quinolinecarboxylate-1 of ethyl[(IX), R₂ =2-OCH₃, n=1, p=0, code: MD 280 524]; yield=81%; meltingpoint=80° C.

chloro-7 cyano-2 tetrahydro-1,2,3,4 quinolinecarboxylate-1 of ethyl[(IX) R₂ =3-Cl, n=1, p=0, code: MD 370 330]; Yield=86%; melting pointfrom 65° C.

EXAMPLE 6 ethoxy-2 tetrahydro-2,3,4,5 1H-benzazepinecarboxylate-1 ofethyl [(XI), R₂ =H, n=2, code: MD 370 012]

A suspension of 0.31 mole (50 g) of tetrahydro-2,3,4,51H-benzazepine-one-2 in 250 ml of THF is added to a suspension of 16.9 gof NaH in 350 ml of THF, then the reaction medium is heated 1 h toreflux. The reaction medium is cooled to 40° C. and 0.62 mole (59.57 ml)of ethyl chloroformate is added, the temperature being maintained at 40°C., and heating is carried out to reflux 1 h. After cooling 20 ml ofethanol is added. The reaction medium is poured on ice. After extractionwith ethyl ether 67% of ethoxycarbonyl-1 tetrahydro-2,3,4,51H-benzazepine-one-2 (melting point=74° C.) is obtained. A solution of0.075 mole (17.5 g) of the latter in 300 ml of ethanol is cooled to -10°C. Bromocresol is added, then simultaneously 60 ml of hydrochloricethanol and 0.225 ml of NaBH₄ (8.55 g), the pH being maintained at 5-6and the temperature at -10° C. Then the temperature is allowed to riseto 20° C. and 20 ml of hydrochloric ethanol (3.1N) is added. Afterconcentration the residue is poured on ice. The aqueous phase isextracted with ethyl ether. The organic phase is dried on sodiumsulphate and concentrated. 17.2 g of product in the form of oil areobtained:

IR ν C=0: 1700 cm⁻¹.

¹ H NMR (CDCl₃) δ ppm: 1 (3H); 1.2 (3H); 1.6-2 (4H); 2.6 (2H); 3.6 (2H);4.2 (2H); 4-6 (1H); 7.1 (4H).

Ethoxy-2 methoxy-7 tetrahydro-2,3,4,5 1H-benzazepinecarboxylate-1 ofethyl [(XI), R₂ =2-OCH₃, n=2, code: MD 370 245] is obtained in the samemanner from corresponding starting materials:

IR ν C=0: 1700 cm⁻¹.

¹ H NMR (CDCl₃) δ ppm: 1 (3H); 1.2 (3H); 1.6-2 (4H); 2.6 (2H); 3.6 (2H);3.7 (3H); 4.2 (2H); 4.3 (1H); 6.6-7.1 (3H).

EXAMPLE 7 cyano-2 methoxy-7 tetrahydro-2,3,4,51H-benzazepinecarboxylate-1 of ethyl [(IX), R₂ =2-OCH₃, n=2, p=0, code:MD 370 246]

0.392 mole (48.6 ml) of trimethylsilyl cyanide and 4.02 g of aluminiumchloride are added at 15° C. to a solution of 0.3 mole (88.5 g) ofethoxy-2 methoxy-7 tetrahydro-2,3,4,5 1H-benzazepinecarboxylate-1 ofethyl [Code: MD 370 245] in 1 liter of methylene chloride. Thetemperature is allowed to rise to 20° C. and after 3 h of agitation thereaction medium is poured on iced water. The organic phase is washedwith the water, dried on sodium sulphate and concentrated. The oilobtained is utilised immediately for the following stage.

Cyano-2 tetrahydro-2,3,4,5 1H-benzazepinecarboxylate-1 of ethyl [(IX),R₂ =H, n=2, p=0, code: MD 370 013]

IR ν C≡N: 2240 cm⁻¹. ν C=0: 1700 cm⁻¹ is obtained in the same way.

EXAMPLE 8 carboxaldehyde-2 tetrahydro-1,2,3,4 quinolinecarboxylate-1 ofethyl [(VIII), R₂ =H, n=1, p=0, code: MD 280 443]

The compound of example 5 (46 g, 0.2 mole) is dissolved in a mediumcontaining acetic acid (330 ml), water (330 ml), pyridine (660 ml) andhydrated sodium hypophosphite (92 g). The solution is heated to 40° C.and Raney nickel (37 g) is added in small quantities in 5 to 6 hours.The catalyst is eliminated by filtration, the filtrate concentrated invacuo. The residue is taken up by water, the product extracted by ether.The organic phase is washed with an aqueous solution saturated withammonium chloride then dried on sodium sulphate. After evaporation ofthe solvent, distillation provides 36.4 g of the expected pure compound.

boiling point under 0.05 mm of Hg: 150° C.,

¹ H NMR (CDCl₃) δ ppm: 1.3 (3H); 1.7 to 2.7 (4H); 4 to 4.5 (2H); 4.5 to4.9 (1H); 6.9 to 7.5 (9H); 7.5 to 8.9 (1H); 9.6 (1H).

IR ν C=0: 1745, 1700 cm⁻¹.

The following compounds (VIII) are obtained in the same way fromcorresponding starting materials:

carboxaldehyde-2 chloro-7 tetrahydro-1,2,3,4 quinolinecarboxylate-1 ofethyl [R₂ =3-Cl, n=1, p=0, code MD 370 331].

¹ H NMR (CDCl₃) δ ppm: 1.3 (3H); 2 (2H); 2.6 (2H); 4.2 (2H); 4.7 (1H);6.8-7.2 (2H); 7.8 (1H); 9.5 (1H).

IR ν C=0: 1753, 1710 and 1700 cm⁻¹.

carboxaldehyde-2 methoxy-6 tetrahydro-1,2,3,4 quinolinecarboxylate-1 ofethyl [R₂ =2-OCH₃, n=1, p=0, code: MD 280 525].

¹ H NMR (CDCl₃) δ ppm: 1.2 (3H); 1.8-2.3 (2H); 2.6 (2H); 3.7 (3H); 4.2(2H); 4.7 (1H); 6.5-6.8 (2H); 7.6 (1H); 9.4 (1H).

IR ν C═0: 1740 and 1700 cm⁻¹.

carboxaldehyde-2 tetrahydro-2,3,4,5 1H-benzazepinecarboxylate-1 of ethyl[R₂ =H, n=2, p=0, code: MD 370 014].

¹ H NMR (CDCl₃) δ ppm: 1.2 (3H); 1.6-2 (2H); 2.7 (2H); 4.2 (2H); 4.8(1H); 7-7.3 (4H); 9.5 (1H).

IR ν C═0: 1740 and 1700 cm⁻¹.

carboxaldehyde-2 methoxy-7 tetrahydro-2,3,4,51H-benzazepinecarboxylate-1 of ethyl [R₂ =2-OCH₃, n=2, p=0, code: MD 370247]

¹ H NMR (CDCl₃) δ ppm: 1.2 (3H); 1.6-2.2 (4H); 2.7 (2H); 3.8 (3H); 4.2(2H); 4.3 (1H); 6.6-6.8 (2H); 7.2 (1H); 9.3 (1H).

IR: ν C=0: 1740 and 1695 cm⁻¹.

EXAMPLE 9 ethoxycarbonyl-1 methoxy-6 tetrahydro-1,2,3,4quinolineethanol-2 [(X), R₂ =2-OCH₃, n=1, p=1, code: MD 370 315]

0.084 mole (1.8 g) of lithium borohydride is added little by little at40° C. to a solution of 0.084 mole (19.4 g) [according to JOC, 16, p.895 (1951)] of ethyl ester of methoxy-6 quinoline-2 acetic acid in 200ml of dimethoxyethane. The reaction medium is heated 5 minutes toreflux. After cooling, the reaction medium is poured on water and theproduct is extracted by methylene chloride. After purification bychromatography on a column of silica (eluent: heptane-ethyl acetate70/30) the product is recrystallised in isopropyl ether (yield=65%;melting point: 88° C.).

1.1 g of platinum oxide is added to a solution of 0.054 mole (11 g) ofthe previous product in 150 ml of methanol with several drops ofhydrochloric ethanol (3N) and a stream of hydrogen is made to bubbletherein for 12 h. After filtration, the organic phase is concentrated.The residue is taken up in methylene chloride. The organic phase iswashed with an aqueous bicarbonate then with water, dried on sodiumsulphate and concentrated. After purification by chromatography (eluent:heptane/ethyl acetate 40/60) 4.7 g of product are obtained in the formof oil. 0.0197 mole of this oil (4.1 g) is dissolved in 100 ml ofchloroform to which is added 0.0394 mole (5.4 g) of potassium carbonateand 0.0237 mole (2.3 ml) of ethyl chloroformate. The reaction medium isheated to reflux for 2 h. After cooling, filtration and concentration,the residue is purified by chromatography on a column of silica (eluent:heptane/ethyl acetate 60/40). The expected product which is obtained isisolated with a yield of 80% in the form of oil.

¹ H NMR (CDCl₃) δ ppm: 1.2 (3H); 1.4 to 1.8 (2H); 2 to 2.8 (4H); 3 to3.7 (3H); 3.7 (3H); 4.2 (2H); 4.7 (1H); 6.5 to 6.8 (9H); 7.2 (1H)

IR:ν OH: 3450 cm⁻¹.

EXAMPLE 10 ethoxycarbonyl-1 methoxy-6 tetrahydro-1,2,3,4 quinoline-2acetaldehyde [(VIII), R₂ =2-OCH₃, n=1, p=1, code: MD 370 316]

0.0292 mole of DMSO in 16 ml of methylene chloride cooled to -60° C. isadded to a solution of 0.016 mole (2 g) of oxalyl chloride in 26 ml ofmethylene chloride, then 0.0146 mole (4.1 g) of the compound obtained inexample 9 is added in solution in 16 ml of methylene chloride. Thenafter 15 minutes 0.073 mole of triethylamine are added in solution in 16ml of methylene chloride. The temperature is allowed to rise to +20° C.The reaction medium is concentrated to dryness and the residue is takenup in a water-methylene chloride mixture. The organic phase is washedwith water, dried on sodium sulphate and concentrated. The expectedproduct which is obtained is isolated in the form of oil afterchromatography on a column of silica (eluent: heptane/ethyl acetate90/10).

Yield: 69%.

IR:ν C=0: 1770 cm⁻¹ and 1745 cm⁻¹.

¹ H NMR (CDCl₃) δ ppm: 1.2 (3H); 1.4 to 1.7 (2H); 2 to 2.8 (4H); 3.7(3H); 4.2 (2H); 5 (1H); 6.5 to 6.8 (2H); 7.3 (1H); 9.5 (1H).

EXAMPLE 11 ethenyl-3 tetrahydro-3,3a,4,5 1H-oxazolo [3,4-a]quinoline-one-1 [(Ia), n=1, p=0, R₂ =H, R₃ =CH=CH₂, cis, code: MD 200502] and [(Ia), n=1, p=0, R₂ =H, R₃ =CH═CH₂, trans, code: MD 200 503]

The magnesium vinyl bromide (0.165 mole) prepared from vinyl bromide(11.6 ml, 0.165 mole) and magnesium (3.86 g, 0.165 mole) in 80 ml oftetrahydrofuran is added drop by drop to a solution of the compound codeMD 280 443 (prepared in example 8) in 350 ml of tetrahydrofuran, kept ata temperature between -20° C. and -40° C. The agitation is maintained1/2 h after the end of the addition, then an aqueous solution saturatedwith ammonium chloride is introduced. The reaction medium is extractedwith ethyl ether, the organic phase washed by an aqueous solutionsaturated with sodium chloride, dried by sodium sulphate, thenevaporated in vacuo. The residue is taken up by 500 ml of toluene andtreated as in example 3 by sodium methylate in order to achievecyclisation. The toluene is then evaporated, the medium taken up bymethylene chloride, washed with water, dried on sodium sulphate thenevaporated. The mixture of two pairs of diastereoisomers obtained (32.6g) is then separated by liquid chromatography on silica.

The least polar product (code: MD 200 503) is constituted by the racemicpair of diastereoisomers of trans relative configuration.

The most polar product (code: MD 200 502) is constituted by the racemicpair of diastereoisomers of cis relative configuration.

EXAMPLE 12 trans hydroxymethyl-3 tetrahydro-3,3a, 4,5 1H-oxazolo [3,4-a]quinoline-one-1 [(Ib), n=1, p=0, R₂ =H, code: MD 200 505]

The trans product code MD 200 503 (2.5 g, 11.6 mmoles) is dissolved in amixture of methanol (45 ml) and methylene chloride (35 ml). A stream ofozone is made to flow for 1 h through the solution cooled to -60° C.(rate of gas flow 0.8 1/mn containing 0.6M of ozone). The temperature ofthe reaction medium is then allowed to rise between -20° C. and -30° C.before the addition of sodium borohydride (7.4 g, 19.7 mmoles). After 30agitation at this temperature, dimethylsulphide (11 ml, 15 mmoles) isadded. The agitation is maintained 3 hours more and the medium isallowed to return to ambient temperature. The reaction medium is pouredon a solution of hydrochloric acid 1N, the product is extracted bymethylene chloride, the organic phase dried on sodium sulphate andevaporated in vacuo. After purification on a column of silica (eluentsystem n-heptane/ethyl acetate 20/80) 2.3 g of the pure expected productis obtained.

EXAMPLE 13 cis methoxymethyl-3 tetrahydro-3,3a,4,5 1H oxazolo [3,4-a]quinoline-one-1 [(Ic), R₄ =OCH₃, R₂ =H, n=1, p=0, code: MD 200 682]

The compound cis hydroxymethyl-3 tetrahydro-3,3a,4,5 1H-oxazolo [3,4-a]quinoline-one-1 [(Ib); code: MD 200 504] (5.6 g, 25.5 g mmoles) is putin suspension in 100 ml of toluene. To this suspension are addedtetrabutyl ammonium bromide (820 mg. 2.5 mmoles), dimethylsulphate (7.2ml, 76 mmoles), then a solution of sodium hydroxide at 50% (127 mmoles).The reaction medium is agitated during one night at ambient temperature,then water (100 ml) is added. The aqueous phase is decanted thenextracted with toluene. The organic phases are collected, dried onsodium sulphate, then evaporated in vacuo. The residue is crystallisedin an ethyl ether/petroleum ether mixture. Flash chromatography onsilica (eluent: n-heptane/ethyl acetate 50/50) provides 4.3 g of thepure expected product.

EXAMPLE 14 methanesulphonate of cis methoxy-7 tetrahydro-3,3a,4,51H-oxazolo [3,4-a] quinoline-one-1 yl-3 methanol [code: MD 370 046]

0.026 mole (3.6 ml) of triethylamine and 0.026 mole (2 ml) of mesylchloride are added to a suspension on cooled to 0° C. of 0.0224 mole(5.6 g) of cis hydroxymethyl-3 methoxy-7 tetrahydro-3,3a,4,5 1H-oxazino[3, 4a] quinoline-one-1 (code: MD 280 386) in 130 ml of methylenechloride. Then the reaction medium is left 1/2 hour at ambienttemperature and poured on water. The organic phase is dried on sodiumsulphate and concentrated. The expected product which is obtained isisolated with a yield of 97% (melting point=164° C.).

The methanesulphonate of trans methoxy-7 tetrahydro-3,3a,4,5 1H-oxazolo[3,4-a] quinoline-one-1 yl-3 methanol [code: MD 370 074] is obtained inthe same way from corresponding starting materials.

Yield: 95%.

Melting point: 177° C.

EXAMPLE 15 trans methyl-3 tetrahydro-3,3a,4,5 1 H-oxazolo [3,4-a]quinoline-one-1 [(Id), R₂ =H, n=1, p=0, R₅ =H, code: MD 280 430]

1.27.10⁻³ mole of tosyl chloride (0.24 g) at 0° C. is added to asolution of 0.9.10⁻³ (0.2 g) of the compound prepared in example 12, in4 ml of pyridine. After 4 h of contact, the reaction medium is poured oniced water and the tosylate obtained is filtered (melting point=186°C.). 1.07.10⁻³ mole of sodium borohydride and 0.5.10⁻³ mole (0.2 g) ofthe preceding tosylate are added to 5 ml of DMSO and heated to 90° C.for 40 minutes. The reaction medium is poured on water and extractedwith ethyl ether. The organic phase is dried on sodium sulphate andconcentrated. The expected product which is obained is isolated with ayield of 72%.

EXAMPLE 16 cis aminomethyl-3 methoxy-7 tetrahydro-3,3a,4,5 1H-oxazolo[3,4-a] quinoline-one-2 [(Id), R₂ =2-OCH₃, n=1 , p=0, R₅ =NH₂, code: MD370 024]

A solution of 0.024 mole (6 g) of methanesulphonate of cis methoxy-7tetrahydro-3,3a,4,5 1H-oxazolo [3,4-a] quinoline-one-1 yl-3 methanol[code: MD 370 046] in 40 ml of methanol and 20 ml of ethanol and 60 mlof liquid ammonia are placed in a pressure-resistant reactor. It isheated to 80° C. for 12 h. The reaction medium is concentrated and theresidue is taken up in methylene chloride. The organic phase is washedin water and in aqueous ammonia, dried and concentrated. The expectedproduct which is obtained is isolated in hydrochloride form with a yieldof 20%.

Using the operational methods given above, but starting from appropriatereactants, the other compounds according to the invention are obtained.The physical characteristics of a certain number of compounds (I) areassembled in Table I which follows; it should be noted that thecompounds listed in this Table occur in the form of racemic pair ofdiastereoisomers of cis or trans relative configuration.

                                      TABLE I    __________________________________________________________________________     ##STR18##                         Con-                                  I.R.                         fig-                            Base            NMR                νC =                         ura-                            or Empirical                                        Mp  Nu-                0    Code        n p R.sub.2                 R.sub.1 tion                            salt                               formula  (°C.)                                            cleus                                               Solvent                                                    δ p.p.m.                                                               cm.sup.-1    __________________________________________________________________________    MD  0 0 H    CH.sub.2 OH                         cis                            base                               C.sub.11 H.sub.11 NO.sub.2                                        128 .sup.1 H                                               DMSOd.sub.6                                                    2.8-3.4(2H);                                                               17302H);    200602                                          4.7-5.2(3H); 6.8-7.4                                                    (4H)    MD  0 0 H    CH.sub.2 OH                         trans                            base                               C.sub.11 H.sub.11 NO.sub.3                                        113 .sup.1 H                                               DMSOd.sub.6                                                    3-3.4(2H);                                                               17402H);    200718                                          4.4-4.8(2H); 5.2(1H);                                                    7-7.4(4H)    MD  0 0 H    CHCH.sub.2                         cis                            base                               C.sub.12 H.sub.11 NO.sub.2                                        74  .sup.1 H                                               CDCl.sub.3                                                    2.6-3.4(2H);                                                               17506.2    200600                                          (5H); 6.8-7.4(4H)    MD  0 0 H    CHCH.sub.2                         trans                            base                               C.sub.12 H.sub.11 NO.sub.2                                        --  .sup.1 H                                               CDCl.sub.3                                                    2.8-3.4(2H);                                                               17605    200601                                          (2H); 5.2-6.4(3H);                                                    6.8-7.4(4H)    MD  1 0 H    CH.sub.2 OH                         cis                            base                               C.sub.12 H.sub.13 NO.sub.3                                        131 .sup.1 H                                               DMSOd.sub.6                                                    1.8-2.2(2H);                                                               17002H);    200504                                          3.6(2H); 4-4.8(2H); 5                                                    (1H); 6.8- 7.3(3H);                                                    8.1(1H)    MD  1 0 H    CH.sub.2 OH                         trans                            base                               C.sub.12 H.sub.13 NO.sub.3                                        138 .sup.1 H                                               CDCl.sub.3                                                    1.5-2.2(2H);                                                               17202H);    200505                                          3.7(2H); 4(1H); 4.3(1H);                                                    5.2(1H); 6.8-7.3(3H);                                                    8.1(1H)    MD  1 0 H    CHCH.sub.2                         cis                            base                               C.sub.13 H.sub.13 NO.sub.2                                        91  .sup.1 H                                               CDCl.sub.3                                                    1.6-2.2(2H);                                                               17402H);    200502                                          3.9-4.3(1H); 4.8-6.2                                                    (4H); 6.8-7.4(3H);                                                    8.2(1H)    MD  1 0 H    CHCH.sub.2                         trans                            base                               C.sub.13 H.sub.13 NO.sub.2                                        121 .sup.1 H                                               CDCl.sub.3                                                    1.6-2.4(2H);                                                               17602H);    200503                                          3.8(1H); 4.6(1H); 5.3-                                                    6.3(3H); 6.8-7.4(3H);                                                    8.3(1H)    MD  1 0 H    CH.sub.2OCH.sub.3                         cis                            base                               C.sub.13 H.sub.15 NO.sub.3                                        113 .sup.1 H                                               CDCl.sub.3                                                    1.6-2.2(2H);                                                               17402H);    200682                                          3.4(3H); 3.6(2H); 4.4-                                                    4.8(2H); 6.8-7.2(3H);                                                    8.1(1H)    MD  1 0 H    CH.sub.2OCH.sub.3                         trans                            base                               C.sub.13 H.sub.15 NO.sub.3                                        69  .sup.1 H                                               CDCl.sub.3                                                    1.5-2.4(2H);                                                               17502H);    200683                                          3.4(3H); 3.6(2H); 3.6-                                                    4.4(2H); 6.8-7.2(3H);                                                    8.1(1H)    MD  1 0 H    C.sub.6 H.sub.5                         cis                            base                               C.sub.17 H.sub.15 NO.sub.2                                        123 .sup.1 H                                               CDCl.sub.3                                                    1-1.8(2H);                                                               17402H);    280389                                          4.2-4.6(1H); 5.7(1H);                                                    7-7.4(8H); 8.2(1H)    MD  1 0 H    C.sub.6 H.sub.5                         trans                            base                               C.sub.17 H.sub.15 NO.sub.2                                        135 .sup.1 H                                               CDCl.sub.3                                                    1.6-2.4(2H);                                                               17502H);    280390                                          3.9(1H); 5.1(1H); 7-7.4                                                    (3H); 8.3(1H)    MD  1 0 H    H       -- base                               C.sub.11 H.sub.11 NO.sub.2                                        95  .sup.1 H                                               CDCl.sub.3                                                    1.1(3H);                                                               17502.2(4H);    280526                                          2.8(2H); 3.9-4.7(2H);                                                    8.1(1H)    MD  1 0 H    CH.sub.3                         cis                            base                               C.sub.12 H.sub.13 NO.sub.2                                        114 .sup.1 H                                               CDCl.sub.3                                                    1.4(3H);                                                               17302.2(2H);    280429                                          2.9(2H); 4.1(1H); 4.8                                                    (1H); 6.8-7.4(3H);                                                    8.2(1H)    MD  1 0 H    CH.sub.3                         trans                            base                               C.sub.12 H.sub.13 NO.sub.2                                        128 .sup.1 H                                               CDCl.sub.3                                                    1.4(3H);                                                               17402.3(2H);    280430                                          2.8(2H); 3.7(1H);                                                    4.4(1H); 6.8-7.3(3H);                                                    8.1(1H)    MD  1 0 H    C.sub.2 H.sub.5                         cis                            base                               C.sub.13 H.sub.15 NO.sub.2                                        114 .sup.1 H                                               CDCl.sub.3                                                    1.1(3H);                                                               17502.3(4H);    280460                                          2.9(2H); 3.6-4.4(2H);                                                    6.8-7.4(3H); 8.2(1H)    MD  1 0 H    C.sub.2 H.sub.5                         trans                            base                               C.sub.13 H.sub.15 NO.sub.2                                        96  .sup.1 H                                               CDCl.sub.3                                                    1.1(3H);                                                               17502.3(4H);    280459                                          2.9(2H); 3.6-4.4(2H);                                                    6.8-7.4(3H); 8.2(1H)    MD  1 0 H    CH.sub.2 N(CH.sub.3).sub.2                         cis                            salt                               C.sub.14 H.sub.19 ClN.sub.2 O.sub.2                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.4(2H);                                                               17458H);    370030                  HCl                     3.6(2H); 4.4(1H);                                                    5.3(1H); 7-7.4(3H); 8(1H)    MD  1 0 H    CH.sub.2 N(CH.sub.3).sub.2                         trans                            salt                               C.sub. 14 H.sub.19 ClN.sub.2 O.sub.2                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.4(2H);                                                               17608H);    370031                  HCl                     3.6(2H); 4(1H); 5(1H);                                                    7-7.4(3H); 8.2(1H)    MD  1 0 3-CH.sub.3                 CH.sub.2 OH                         cis                            base                               C.sub.13 H.sub.15 NO.sub.3                                        160 .sup.1 H                                               CDCl.sub.3                                                    2.1(2H);                                                               17153H);    370032                                          2.9(2H); 3.8(3H);                                                    4.3(1H);                                                    4.7(1H); 6.8-7.2(2H);                                                    8(1H)    MD  1 0 3-CH.sub.3                 CH.sub.2 OH                         trans                            base                               C.sub.13 H.sub.15 NO.sub.3                                        139 .sup.1 H                                               CDCl.sub.3                                                    1.8-2.4(2H);                                                               17153H);    370033                                          2.9(2H); 3.9(3H);                                                    4.2(1H); 4.6(1H);                                                    6.7-7.3(2H);                                                    8(1H)    MD  1 0 3-Cl CH.sub.2 OH                         cis                            base                               C.sub.12 H.sub.12 ClNO.sub.3                                        172 .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.4(2H);                                                               17202H);    370336                                          3.7(2H); 4-4.8(2H);                                                    5.2(1H); 6.9-7.3(2H);                                                    8.2(1H)    MD  1 0 3-Cl CH.sub.2 OH                         trans                            base                               C.sub.12 H.sub.12 ClNO.sub.3                                        152 .sup.1 H                                               DMSOd.sub.6                                                    1.5-2.4(2H);                                                               17302H);    370335                                          3.6-4.5(4H); 5.2(1H);                                                    6.9-7.3(2H); 8.1(1H)    MD  1 1 2-OCH.sub.3                 CH.sub.2 OH                         most                            base                               C.sub.14 H.sub.17 NO.sub.4                                        144 .sup.1 H                                               CDCl.sub.3                                                    1.7-2.6(5H);                                                               17202H);    370038               polar                      3.8(6H); 4.5(1H); 6.6-                                                    6.8(2H); 7.8(1H)    MD  1 1 2-OCH.sub.3                 CH.sub.2 OH                         least                            base                               C.sub.14 H.sub.17 NO.sub.4                                        177 .sup.1 H                                               CDCl.sub.3                                                    1.6-2.4(5H);                                                               17302H);    370039               polar                      3.8(6H); 4.4(1H), 6.6-                                                    6.8(2H); 7.7(1H)    MD  1 0 2-OCH.sub.3                 CHCH.sub.2                         cis                            base                               C.sub.14 H.sub.15 NO.sub.3                                        100 .sup.1 H                                               CDCl.sub.3                                                    1.7-2.1(2H);                                                               17602H);    280403                                          3.8(3H); 4.2(1H); 4.9-                                                    6(4H); 6.6-6.8(2H);                                                    8(1H)    MD  1 0 2-OCH.sub.3                 CHCH.sub.2                         trans                            base                               C.sub.14 H.sub.15 NO.sub.3                                        134 .sup.1 H                                               CDCl.sub.3                                                    1.4-2.4(2H);                                                               17502H);    280404                                          3.7(4H); 4.5(1H); 5.2-                                                    6.2(3H); 6.6-6.8(2H);                                                    8.1(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2 OH                         cis                            base                               C.sub.13 H.sub.15 NO.sub.4                                        162 .sup.1 H                                               DMSOd.sub.6                                                    2.1(2H); 2.9(2H);                                                               1720    280386                                          4.8(8H); 6.6-6.8(2H);                                                    8(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2 OH                         trans                            base                               C.sub.13 H.sub.15 NO.sub.4                                        147 .sup.1 H                                               DMSOd.sub.6                                                    2(2H); 2.8(2H);                                                               17204.4    280387                                          (7H); 5.2(1H); 6.6-6.9                                                    (2H); 8(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2OCH.sub.3                         cis                            base                               C.sub.14 H.sub.17 NO.sub.4                                        99  .sup.1 H                                               CDCl.sub.3                                                    2(2H); 2.8(2H);                                                               1740    280448                                          3.3(3H); 3.6(2H);                                                    3.8(3H);                                                    4.2(1H); 4.7(1H);                                                    6.6-6.8(2H);                                                    8(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2OCH.sub.3                         trans                            base                               C.sub.14 H.sub.17 NO.sub.4                                        105 .sup.1 H                                               CDCl.sub.3                                                    1.6-2.4(2H);                                                               17502H);    280449                                          3.4(3H); 3.6-4.4(7H);                                                    6.6-6.8(2H); 8.1(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2NH.sub.2                         cis                            salt                               C.sub.13 H.sub.17 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    2(2H); 2.8(2H);                                                               1760    370024                  HCl                               6.2% H.sub.2 O       3.2(2H); 3.7(3H);                                                    4.3(1H);                                                    5(1H); 6-6.8(2H); 7.9(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2NH.sub.2                         trans                            salt                               C.sub.13 H.sub.17 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.2(2H);                                                               17602H);    370025                  HCl                               4.8% H.sub.2 O       3.3(2H); 3.6(3H);                                                    4(1H); 4.5(1H);                                                    6.6-6.8(2H);                                                    7.9(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2NHCH.sub.3                         cis                            HCl                               C.sub.14 H.sub.19 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    2(2H); 2.6(3H);                                                               1750    370026                                          2.8(3H); 3.4(2H);                                                    3.7(3H);                                                    4.4(1H); 5.2(1H);                                                    6.1-7(2H);                                                    7.9(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2NHCH.sub.3                         trans                            salt                               C.sub.14 H.sub.19 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.4(2H);                                                               17503H);    370027                  HCl                     2.8(2H); 3.4(2H);                                                    3.7(3H); 4(1H); 4.7(1H);                                                    6.6-6.9                                                    (2H); 7.9(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2 N(CH.sub.3).sub.2                         cis                            salt                               C.sub.15 H.sub.21 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.6-2.4(2H);                                                               17408H);    370028                  HCl                     3.6(2H);                                                               17603H);                                                    4.4(1H); 5.4(1H);                                                    6.6-6.9(2H);                                                    7.8(1H)    MD  1 0 2-OCH.sub.3                 CH.sub.2 N(CH.sub.3).sub.2                         trans                            salt                               C.sub.15 H.sub.21 ClN.sub.2 O.sub.3                                        >250                                            .sup.1 H                                               DMSOd.sub.6                                                    1.5-2.4(2H);                                                               17608H);    370029                  HCl                               5.12% H.sub.2 O      3.3-4.1(6H); 4.9(1H);                                                    6.6-6.9(2H); 8(1H)    MD  2 0 H    CH.sub.2 OH                         cis                            base                               C.sub.13 H.sub.15 NO.sub.3                                        170 .sup.1 H                                               DMSOd.sub.6                                                    1.1-2.2(4H);                                                               1730    370067                                          2.5-3(2H); 3.5-4(3H);                                                    4.7(1H);                                                               1750                                                    (1H); 7-7.5(4H)    MD  2 0 2-OCH.sub.3                 CH.sub.2 OH                         cis                            boase                               C.sub.14 H.sub.17 NO.sub.4                                        120 .sup.1 H                                               DMSOd.sub.6                                                    1-2.2(4H); 2.7(2H);                                                               1730    370022                                          (6H); 4.6(1H); 5(1H);                                                    6.6-6.8(2H); 7.2(1H)    MD  2 0 2-OCH.sub.3                 CH.sub.2 OH                         trans                            base                               C.sub.14 H.sub.17 NO.sub.4                                        200 .sup.1 H                                               DMSO 1.2-2.2(4H);                                                               17302H);    370023                                          3.5(3H); 3.7(3H);                                                    4.2(1H); 5(1H);                                                    6.6-6.8(2H);                                                    7.1(1H)    MD  1 1 2-OCH.sub.3                 CHCH.sub.2                         least                            base                               C.sub.15 H.sub.17 NO.sub.3                                        140 .sup.1 H                                               CDCl.sub.3                                                    1.2-2.2(4H);                                                               16802H);    370317               polar                      3.4-3.7(1H); 3.7(3H);                                                    4.6-4.9(1H); 5.1-6.2                                                    (3H); 6.5-6.9(2H);                                                    7.6(1H)    MD  1 1 2-OCH.sub.3                 CHCH.sub.2                         most                            base                               C.sub.15 H.sub.17 NO.sub.3                                        106 .sup.1 H                                               CDCl.sub.3                                                    1.8-2.3(4H);                                                               16902H);    370318               polar                      3.4-3.7(1H); 3.7(3H);                                                    4.6-6.3(4H); 6.5-6.9                                                    (2H); 7.8(1H)    MD  2 0 H    CHCH.sub.2                         cis                            base                               C.sub.14 H.sub.15 NO.sub.2                                        131 .sup.1 H                                               CDCl.sub.3                                                    1.2-2.3(4H);                                                               17502H);    370017                                          3.4-3.9(1H); 5-6.3                                                    (4H); 7-7.5(4H)    MD  2 0 H    CHCH.sub.2                         trans                            base                               C.sub.14 H.sub.15 NO.sub.2                                        95  .sup.1 H                                               CDCl.sub.3                                                    1-2.3(4H);                                                               17502.9    370018                                          (2H); 3.1-3.5(1H); 4.6                                                    (1H); 5.1-6.3(3H);                                                    7-7.6(4H)    MD  1 0 3-Cl CHCH.sub.2                         trans                            base                               C.sub.13 H.sub.12 ClNO.sub.2                                        oil .sup.1 H                                               CDCl.sub.3                                                    1.2-2.2(2H);                                                               1750    370333                                          2.6-3(2H); 3.9-4.4(1H);                                                    5.9-6.2                                                    (4H); 6.8-7.2(2H);                                                    8.2(1H)    MD  1 0 3-Cl CHCH.sub.2                         cis                            base                               C.sub.13 H.sub.12 ClNO.sub.2                                        oil .sup.1 H                                               CDCl.sub.3                                                    1-2.5(2H); 1750    370334                                          2.7-3.1(2H); 3.5-4(1H);                                                    4.5-4.7(1H); 5.3-6.3(3H);                                                    7(3H);                                                    8.4(1H)    MD  1 0 3-CH.sub.3                 CHCH.sub.2                         cis                            base                               C.sub.14 H.sub.15 NO.sub.2                                        oil .sup.1 H                                               CDCl.sub.3                                                    1.2-2.2(2H);                                                               --3(3H);    370240                                          2.7-3.1(2H); 3.8-4.4                                                    (1H); 4.9-6.3(4H); 6.7-                                                    7.2(2H); 8.0(1H)    MD  1 0 3-CH.sub.3                 CHCH.sub.2                         trans                            base                               C.sub.14 H.sub.15 NO.sub.2                                        oil .sup.1 H                                               CDCl.sub.3                                                    1.2-2.4(2H);                                                               --4(3H);    370239                                          2.7-3.1(2H);                                                    3.5-4(1H); 4.6(1H);                                                    5.3-6.3(3H);                                                    6.7-7.2(2H); 8.1(1H)    MD  2 0 2-OCH.sub.3                 CHCH.sub.2                         cis                            base                               C.sub.15 H.sub.17 NO.sub.3                                        175 .sup.1 H                                               CDCl.sub.3                                                    1-2.3(4H);    370250                                          2.5-2.9(2H); 3.4-3.8(1H);                                                    3.8(3H);                                                    5-6.3(4H); 6.6-6.9                                                    (2H); 7.2(1H);    MD  2 0 2-OCH.sub.3                 CHCH.sub.2                         trans                            base                               C.sub.15 H.sub.17 NO.sub.3                                        123 .sup.1 H                                               CDCl.sub.3                                                    1.1-2.3(4H);                                                               17502.9    370251                                          (2H); 3.1-3.5(1H);                                                    3.7(3H); 4.5(1H); 5.1                                                    -6.3(3H); 6.6-6.9(2H);                                                    7.3(1H)    __________________________________________________________________________     In table I, Mp means melting point

The compounds of formula (I) and their physiologically acceptable saltshave been tested in vitro and in vivo and have been shown to have aninteresting therapeutic activity. In particular these compounds andsalts have proved active as inhibitors of the monoamine oxydase andcapable of potentiating the effects of serotonin when it is administeredto animals in the form of the precursor hydroxy-5 tryptophan.

This activity has been demonstrated:

in vitro on homogenates of rat brain, by measuring the concentration ofthe product inhibiting by 50% (IC₅₀) the activity of the monoamineoxydase utilising serotonin as substrate at 480 μM, according to themethod described by M. STROLIN BENEDETTI. T. BOUCHER and C. J. FOWLER inNaunyn--Schmiedebergs Archiv. of Pharm. (1983) 323, 315-320;

in vivo by determining in rats the dose of the product which,administered orally, causes in 50% of the animals (ED₅₀) the appearanceof generalised trembling or stereotypies (finger-tapping as on a piano,movements of the head) following the intraperitoneal administration 1 hafter the first treatment of a dose of 120 mg/kg of hydroxy-5 tryptophan(5-HTP) [M. JALFRE, B. BUCHER, A. COSTON, G. MOCQUET, R. D. PORSOLT,Arch. Int. Pharmacodyn., (1982), 259, 194-221].

The activity of some compounds of the invention are given in followingTable II for illustrating the invention.

                  TABLE II    ______________________________________    Compound tested                  Test in vivo   Test in vitro    Code No.      ED.sub.50 (mg/kg/p.o.)                                 IC.sub.50 (μm)    ______________________________________    MD 280430     105            1.4    MD 200682     2.3            0.09    MD 280404     11             0.029    MD 200602                    2.8    MD 200718                    8.7    MD 200502                    0.5    MD 200503     20             0.057    MD 200504     7.8    MD 280448     1.8            0.009    MD 280449                    0.006    MD 370024                    1    MD 370025                    1.6    MD 370027     5.8    MD 280386                    0.019    MD 280387                    0.075    MD 370336                    0.08    MD 370335                    0.097    ______________________________________

Moreover, no particular toxic signs were noted in the rodent byadministration of the compounds according to the invention at the dosesat which they demonstrate a pharmacological activity. Thus, for example,the compounds MD 280 449 and MD 370 026 have a LD₅₀ in mice respectivelyof 1120 and 263 mg/kg/p.o.

The above data show the therapeutic interest of the compounds of formula(I) and their physiologically acceptable salts according to theinvention. Thus these compounds and salts find their application asmedicaments for humans and for animals, particularly for the treatmentof depressive states.

The present invention also extends to pharmaceutical or veterinarycompositions containing at least one of the said compounds and salts, aswell as one or more physiologically acceptable vehicles. Thesecompositions can be formulated with a view to oral administration andthen they are presented for example in the form of sugar-coated pills,capsules, tablets or solutions to be drunk, or with a view to parenteraladministration and then they are presented as injectable solutions.

Finally, the doses at which the compounds according to the invention canbe administrated will depend particularly upon the means ofadministration, the body weight of the patient, the state of the latterand the therapeutic power of the compounds used. Generally the dosescould reach 1 to 50 mg/kg/day, taken in one or more times.

We claim:
 1. An oxazoloquinoline compound of the formula: ##STR19## or apharmaceutically acceptable mineral or organic acid addition saltthereof, wherein:R₁ is a hydrogen atom; a C₁ -C₄ alkyl group; a phenylgroup; a C₂ -C₃ alkenyl group; or a methyl group substituted by ahydroxy group, a C₁ -C₄ alkoxy group, an amino group, a N-(C₁ -C₄) alkylamino group or a N,N-di(C₁ -C₄) alkylamino group; and R₂ is a hydrogenatom; a halogen atom; a C₁ -C₄ alkyl group or a C₁ -C₄ alkoxy group. 2.A pharmaceutical composition for use as an antidepressant agentcomprising a therapeutically effective amount of an oxazoloquinolinecompound or acid addition salt thereof of claim 1 and a pharmaceuticallyacceptable carrier.
 3. A method for the treatment of depressive statesin humans or animals, which comprises administering to a human or animalin need of such treatment an effective amount of an oxazoloquinolinecompound or acid addition salt thereof of claim
 1. 4. The compound ofclaim 1, wherein R₁ is a methoxymethyl group and R₂ is a 2-methoxygroup.
 5. The compound of claim 1, wherein R₁ is a hydroxymethyl groupand R₂ is a 2-methoxy group.
 6. The compound of claim 1, wherein R₁ is amethoxymethyl group and R₂ is a hydrogen atom.
 7. The compound of claim1, wherein R₁ is a methylaminomethyl group and R₂ is a 2-methoxy group.8. The compound of claim 1, wherein R₁ is a ethenyl group and R₂ is a2-methoxy group.